Identifying specific genes that predispose to psychiatric illness is a major goal of genetic research, because the metabolic characterization of such genes and the eventual understanding of how environmental factors interact with these genes will lead to primary preventive measures and improved treatment. In the autosomal recessive Wolfram Syndrome (WS), defined by diabetes mellitus and bilateral optic atrophy, 24% of adolescent and young adult homozygotes have severe psychiatric hospitalizations. The WS gene will be mapped with DNA polymorphisms, using available and newly found genetically informative families, and cloned after fine mapping and chromosome walking and jumping. The metabolic action of this gene that predisposes to psychiatric illness can then be characterized through "reverse genetics." Further, characterizing the WS gene is of even greater importance because the observed excess of psychiatric illness in WS blood relatives is evidence that WS heterozygotes, constituting about one percent of the general population, are predisposed to psychiatric illness. Once WS allele-specific or tightly linked highly polymorphic probes are available, this association will be tested using a newly developed rigorous method that compares, in the group of WS blood relatives with the most severe psychiatric illness, the observed proportion of WS heterozygotes to that expected on the basis of family relationships and the allele frequency. Confirming the association and understanding the metabolic action of the WS gene will lead to effective primary prevention of, or treatment for, psychiatric illness in the substantial proportion of the general population who are WS heterozygotes.